Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy.
Ya-Li SangChristophe PannecouqueErik De ClercqShuai WangXiangtao ChenPublished in: Journal of medicinal chemistry (2023)
To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) 4 , a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC 50 = 2.3 nM) and five mutant strains, such as K103N (EC 50 = 8 nM) and E138K (EC 50 = 6 nM), significantly better than 4 . The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC 50 = 40.77 μM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- wild type
- hiv testing
- human immunodeficiency virus
- hiv aids
- hepatitis c virus
- photodynamic therapy
- men who have sex with men
- hiv infected patients
- escherichia coli
- oxidative stress
- liver failure
- structure activity relationship
- anti inflammatory
- respiratory failure
- computed tomography
- acute respiratory distress syndrome
- extracorporeal membrane oxygenation
- light emitting
- mechanical ventilation
- ionic liquid
- combination therapy
- replacement therapy